title: Evaluation of serum bile acid profiles as biomarkers of liver injury in rodents.
abstract: Bile acids (BAs) have been studied as potential biomarkers of drug-induced liver injury. However, the relationship between levels of individual BAs and specific forms of liver injury remains to be fully understood. Thus, we set out to evaluate cholic acid (CA), glycocholic acid (GCA), and taurocholic acid (TCA) as potential biomarkers of liver injury in rodent toxicity studies. We have developed a sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay applicable to rat and mouse serum and evaluated levels of the individual BAs in comparison with the classical biomarkers of hepatotoxicity (alanine aminotransferase [ALT], aspartate aminotransferase [AST], glutamate dehydrogenase (GLDH), alkaline phosphatase, total bilirubin, gamma-glutamyl transferase, and total BAs) and histopathology findings in animals treated with model toxicants. The pattern of changes in the individual BAs varied with different forms of liver injury. Animals with histopathologic signs of hepatocellular necrosis showed increases in all 3 BAs tested, as well as increases in ALT, AST, GLDH, and total BAs. Animals with histopathologic signs of bile duct hyperplasia (BDH) displayed increases in only conjugated BAs (GCA and TCA), a pattern not observed with the other toxicants. Because BDH is detectable only via histopathology, our results indicate the potential diagnostic value of examining individual BAs levels in serum as biomarkers capable of differentiating specific forms of liver injury in rodent toxicity studies.
authors.affiliation: * Biomarkers of Drug Safety Research and Development and.
authors.forename: Lina
authors.initials: L
authors.lastname: Luo
authors.forename: Shelli
authors.initials: S
authors.lastname: Schomaker
authors.forename: Christopher
authors.initials: C
authors.lastname: Houle
authors.forename: Jiri
authors.initials: J
authors.lastname: Aubrecht
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Colangelo
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood*; D001652:Bile Ducts / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis / Q000209:etiology; D019826:Cholic Acid / Q000097:blood; D002853:Chromatography, Liquid; D004796:Clinical Enzyme Tests; D004195:Disease Models, Animal; D004798:Enzymes / Q000097:blood; D006000:Glycocholic Acid / Q000097:blood; D006965:Hyperplasia; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009336:Necrosis; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry; D013656:Taurocholic Acid / Q000097:blood
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; D004798:Enzymes; D013656:Taurocholic Acid; D019826:Cholic Acid; D006000:Glycocholic Acid
keywords: LC/MS/MS; bile acids; bile duct hyperplasia; biomarkers.; drug-induced liver necrosis